Magnetic resonance imaging (MRI) is a nuclear magnetic resonance (NMR) technique that may be used clinically to differentiate between normal and abnormal tissues. The .sup.1 H NMR imaging method is based upon differences in water proton concentrations and relaxation rates within different tissue types.
When magnetic resonance imaging was first being developed as a diagnostic tool, it was believed that there would be no need for a contrast agent and, that by the use of carefully selected pulse sequences, it would be possible to differentiate tissue types and provide accurate diagnoses. See, Wolf, C. L., Burnett, K. R., Goldstein, U. & Joseph P. M. Magn. Res. Ann. 1985, 231. In many areas of diagnostic medicine this has been found not to be the case, leading to contrast agents being developed.
Contrast agents function in such a way that they lead to the alteration of an image so that, if localized within, say, a tumor, the signal intensity due to the water protons within the tumor becomes different from that of the surrounding tissue. There are two ways in which these alterations can be made. The signal can become brighter or the signal can become darker, and both of these effects are obtainable using various types of contrast agents.
Nearly all of the classes of contrast agent create their desired effect by changing the spin-lattice relaxation time (T.sub.1) and/or the spin-spin relaxation time (T.sub.2) of the water protons (one notable exception is the family of diamagnetic fluorocarbons, which finction by replacing water, thus leading to a null signal for that region). See, Wood, M. L. & H. P.A.J. Mag. Reson. Imag. 1993, 3, 149. See, Lauffer, R. B. Invest. Radiol. 1990, 25, S32. Those contrast agents that operate predominantly on spin-spin relaxation times are the superparamagnets, such as particulate iron oxides. Those contrast agents that operate predominantly on the spin-lattice relaxation time are the paramagnets. These species possess unpaired electrons and thus have a net magnetic moment. It is this magnetic moment which leads to an increase in the spin-lattice relaxation rate of water protons, as the magnetic moment stimulates the transition from a high-energy spin state to a lower energy spin state. For contrast-enhanced MR imaging it is desirable to have a large magnetic moment, with a relatively long electronic relaxation time. Based upon these criteria, candidates for use in contrast agents include Gd(III), an f.sup.7 system, and the d.sup.5 systems Mn(H) and high-spin Fe(III). Gadolinium(III) has the largest magnetic moment among these three and it has been extensively studied.
It might seem that the aqua ion of each of these paramagnetic metals would be a good choice for use as a contrast agent, as these have the largest possible number of bound water molecules. However, the aqua ions are relatively toxic, and there exists little opportunity to control the biodistribution of these species. The reported LD.sub.50 values for the metal chloride salts in aqueous solution are 1.4, 1.5 and 1.6 mmol/kg for gadolinium, manganese and iron respectively when administered to mice i.p. See, Lauffer, R. B. Chem. Rev. 1987, 87, 901.
In attempts to solve both of these problems, a variety of ligands--organic molecules which are able to coordinate to the metal ions--have been employed. For current clinical contrast agents that are based on gadolinium, ligands are employed which occupy almost all of the coordination sites on the metal ion, typically leaving one site available for water molecules to reversibly bind. This approach reduces the toxicity of the metal ion and, by careful variation of the ligand system, potentially allows control of the biodistribution such that in vivo targeting may be achieved. Other desirable properties of a potential contrast agent may include prompt clearance of an extracellular agent as well as in vivo and in vitro stability.
It will be appreciated that there are potential advantages with the use of manganese and iron in comparison to gadolinium because both iron and manganese have a natural human biochemistry which may make it simpler to design target-specific contrast agents based on known biochemical uptake mechanisms, i.e., tissue specificity.
Another problem to overcome is the choice of ligand system. More particularly, it is desirable to provide a ligand system that will reduce the toxicity to an acceptable level, and give the in vivo desired targeting.
It will be appreciated from the foregoing that there is still a significant need for a tissue-specific contrast agent for image enhancement in magnetic resonance imaging that addresses at least some of the problems of the prior art. It is another object of the present invention to provide a tissue-specific contrast agent for image enhancement in magnetic resonance imaging having toxicity levels no greater than clinical agents currently used, e.g., Gd-DTPA (gadolinium ion chelated with the ligand diethylenetriaminepentaacetic acid). Yet another object of the present invention is to provide a tissue-specific contrast agent for image enhancement of tumors. Still another object of the present invention is to provide a tissue-specific contrast agent for image enhancement of tumors, necrotic tissue and/or necrotic tumor tissue. Another object of the present invention is to provide a tissue-specific contrast agent for image enhancement to provide precise localization and sizing of the tissue.